Affinage

OXSR1

Serine/threonine-protein kinase OSR1 · UniProt O95747

Length
527 aa
Mass
58.0 kDa
Annotated
2026-06-10
15 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OXSR1 is a serine/threonine kinase that operates as the effector arm of an osmosensing WNK kinase cascade, transducing osmotic and injury signals into ion-homeostatic and cytoskeletal responses [PMID:bio_10.1101_2024.12.12.628181]. Under osmotic stress, the NRBP1 pseudokinase associates with WNK1 and is required for activation of WNK1 and its downstream effector OXSR1, which engages WNK and SPAK through a conserved CCT domain that mediates complex assembly [PMID:bio_10.1101_2024.12.12.628181]. In the intestine, injury-activated OXSR1 phosphorylates RhoB GTPase at threonine 37, disrupting RhoB's interaction with ARHGAP17 and raising GTP-bound RhoB, thereby driving F-actin polymerization and YAP activation to promote regeneration (PMID:41851502). The same WNK1-OXSR1 axis controls red blood cell hydration through phosphorylation of the downstream KCC3 (SLC12A6) transporter, with OXSR1 loss increasing RBC density [PMID:bio_10.1101_2025.09.20.677403]. OXSR1 also restrains innate immune signaling: by limiting potassium efflux it suppresses NLRP3 inflammasome activation, caspase-mediated IL-1β release, and TNF-α during mycobacterial infection (PMID:35545295). OXSR1 expression is itself regulated post-transcriptionally, being reduced by FTO-mediated m6A modification of its mRNA (PMID:39739936).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2022 High

    Established that OXSR1 functions as a brake on innate immune signaling by maintaining intracellular potassium, linking its kinase activity to inflammasome control rather than only ion transport.

    Evidence Genetic depletion and pharmacological inhibition in zebrafish (M. marinum) and THP-1 cells (M. tuberculosis) with potassium, caspase, IL-1β, TNF-α, and bacterial burden readouts

    PMID:35545295

    Open questions at the time
    • Direct kinase substrate mediating potassium retention not identified
    • Whether the WNK upstream input governs this immune role untested
  2. 2024 Medium

    Defined the upstream activation logic of OXSR1, showing NRBP1 is required for osmotic-stress activation of WNK1 and downstream OXSR1 and that OXSR1's CCT domain mediates assembly into the WNK-SPAK complex.

    Evidence Proximity ligation, reciprocal Co-IP, mass spectrometry, NRBP1 knockdown/knockout, in vitro kinase activation with recombinant proteins, and AlphaFold-3 modeling (preprint)

    PMID:bio_10.1101_2024.12.12.628181

    Open questions at the time
    • Single preprint not peer-reviewed
    • Physiological contexts requiring NRBP1-dependent activation undefined
  3. 2024 Medium

    Showed OXSR1 abundance is set post-transcriptionally, identifying FTO-mediated m6A modification of OXSR1 mRNA as a regulatory input in LPS-induced kidney injury.

    Evidence MeRIP and RIP assays, overexpression/knockdown rescue in HK2 cells and CLP mouse model

    PMID:39739936

    Open questions at the time
    • m6A reader mediating OXSR1 mRNA fate not identified
    • Single study, kinase-pathway connection to the injury phenotype not dissected
  4. 2025 Medium

    Placed OXSR1 in a defined WNK1-OXSR1-KCC3 axis governing red blood cell hydration, connecting its kinase activity to a specific physiological transporter substrate.

    Evidence Pooled CRISPR screen with density-gradient selection and phosphoproteomics in OXSR1-depleted erythroid cells (preprint)

    PMID:bio_10.1101_2025.09.20.677403

    Open questions at the time
    • Single preprint not peer-reviewed
    • Direct phosphorylation of KCC3 by OXSR1 not reconstituted in vitro
  5. 2026 High

    Identified RhoB T37 as a direct OXSR1 substrate and connected the WNK-OXSR1 cascade to Hippo-YAP-driven tissue regeneration, defining a cytoskeletal output of the kinase beyond ion transport.

    Evidence Drosophila and mouse intestinal injury models, phosphoproteomics, Co-IP, genetic and pharmacological perturbation, IBD patient samples

    PMID:41851502

    Open questions at the time
    • How osmolarity sensing is transduced to OXSR1 in this context not resolved
    • Generality of RhoB phosphorylation across non-intestinal tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how OXSR1 selects among its divergent outputs (KCC3-driven ion homeostasis, RhoB-driven cytoskeletal remodeling, potassium-dependent inflammasome control) in different cellular contexts.
  • No unified model of context-dependent substrate choice
  • Spatial/temporal regulation of the WNK-OXSR1 complex not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 1
Partners
ARHGAP17KCC3NRBP1RHOBSPAKWNK1
Complex memberships
WNK-OXSR1-SPAK complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2026 OXSR1 phosphorylates RhoB GTPase at threonine 37 upon intestinal injury, disrupting its interaction with ARHGAP17 and increasing GTP-bound RhoB levels, which leads to enhanced F-actin polymerization and YAP activation to promote intestinal regeneration. This positions OXSR1 as part of the osmolarity-sensing WNK-OXSR1 kinase cascade that mediates intestinal regeneration via Hippo-YAP signaling. Drosophila and mouse intestinal injury models, phosphoproteomics, co-immunoprecipitation, genetic loss-of-function, pharmacological inhibition, IBD patient samples The EMBO journal High 41851502
2022 OXSR1 inhibits NLRP3 inflammasome activation during mycobacterial infection by limiting potassium efflux. Genetic depletion or pharmacological inhibition of OXSR1 decreases intracellular potassium levels, triggering NLRP3 inflammasome activation, caspase-mediated IL-1β release, and downstream TNF-α activation, thereby reducing bacterial burden. Genetic depletion and pharmacological inhibition of OXSR1 in zebrafish embryos (M. marinum) and THP-1 cells (M. tuberculosis), measurement of intracellular potassium, inflammasome activation assays, cytokine quantification Life science alliance High 35545295
2025 Deletion of OXSR1 in erythroid cells increases red blood cell density, and phosphoproteome analysis in OXSR1-depleted cells revealed dephosphorylation of the upstream kinase WNK1 and the downstream target KCC3 (SLC12A6), placing OXSR1 in the WNK1-OXSR1-KCC3 signaling axis controlling RBC hydration. Pooled CRISPR screens in erythroid cell line, density gradient selection, phosphoproteomics in OXSR1-depleted cells bioRxivpreprint Medium bio_10.1101_2025.09.20.677403
2024 OXSR1 is a downstream kinase of the WNK pathway that is activated in response to osmotic stress. The NRBP1 pseudokinase associates with WNK1 under osmotic stress and is required for activation of WNK1 and downstream OXSR1; OXSR1 contains a conserved CCT domain that participates in complex assembly with WNK and SPAK. Proximity ligation, co-immunoprecipitation, mass spectrometry, immunoblotting, knockdown/knockout of NRBP1, in vitro kinase activation assay with recombinant proteins, AlphaFold-3 structural modeling bioRxivpreprint Medium bio_10.1101_2024.12.12.628181
2024 FTO (fat mass and obesity-associated protein) decreases OXSR1 expression through m6A modification of OXSR1 mRNA, as demonstrated by MeRIP and RIP assays, and overexpression of OXSR1 reverses the protective effects of FTO in LPS-induced kidney cell injury. MeRIP assay, RIP assay, Western blot, qRT-PCR, overexpression and knockdown experiments in HK2 cells and CLP mouse model The Kaohsiung journal of medical sciences Medium 39739936
2022 OXSR1 is a direct target of miR-455-3p as validated by dual luciferase reporter assay; knockdown of OXSR1 attenuates copper-induced autophagy in hepatocytes, placing OXSR1 downstream of miR-455-3p in a pathway regulating autophagy under copper stress. Dual luciferase reporter assay, OXSR1 knockdown in broiler hepatocytes and cell lines, autophagy marker analysis (Beclin1, Atg5, LC3), in vivo copper exposure model Chemico-biological interactions Low 36372260

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Knockdown of circ-FANCA alleviates LPS-induced HK2 cell injury via targeting miR-93-5p/OXSR1 axis in septic acute kidney injury. Diabetology & metabolic syndrome 51 33468219
2020 MicroRNA-25-3p suppresses epileptiform discharges through inhibiting oxidative stress and apoptosis via targeting OXSR1 in neurons. Biochemical and biophysical research communications 24 31954517
2022 Suppression of lncRNA GAS6-AS2 alleviates sepsis-related acute kidney injury through regulating the miR-136-5p/OXSR1 axis in vitro and in vivo. Renal failure 16 35793478
2022 LncRNA ZFAS1 regulates the hippocampal neurons injury in epilepsy through the miR-15a-5p/OXSR1/NF-κB pathway. Metabolic brain disease 13 35751788
2022 Long-term copper exposure caused hepatocytes autophagy in broiler via miR-455-3p-OXSR1 axis. Chemico-biological interactions 11 36372260
2022 OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection. Life science alliance 10 35545295
2023 CircNRIP1 KNOCKDOWN ALLEVIATES LIPOPOLYSACCHARIDE-INDUCED HUMAN KIDNEY 2 CELL APOPTOSIS AND INFLAMMATION THROUGH miR-339-5p/OXSR1 PATHWAY. Shock (Augusta, Ga.) 9 36609531
2022 Long non-coding RNA PVT1 regulates LPS-induced acute kidney injury in an in vitro model of HK-2 cells by modulating the miR-27a-3p/OXSR1 axis. Experimental and therapeutic medicine 9 35978931
2024 Curcumin-induced exosomal FTO from bone marrow stem cells alleviates sepsis-associated acute kidney injury by modulating the m6A methylation of OXSR1. The Kaohsiung journal of medical sciences 8 39739936
2021 LINC01291 promotes hepatocellular carcinoma development by targeting the miR-186-5p/OXSR1 axis. The journal of gene medicine 8 34665488
2023 CIRC_0002131 CONTRIBUTES TO LPS-INDUCED APOPTOSIS, INFLAMMATION, AND OXIDATIVE INJURY IN HK-2 CELLS VIA INHIBITING THE BINDING BETWEEN MIR-942-5P AND OXSR1. Shock (Augusta, Ga.) 5 37549022
2022 Association of genetic variants of oxidative stress responsive kinase 1 (OXSR1) with asthma exacerbations in non-smoking asthmatics. BMC pulmonary medicine 5 34983467
2022 Silencing of long non-coding RNA ZFAS1 alleviates LPS-induced acute lung injury by mediating the miR-96-5p/OXSR1 axis in sepsis. The American journal of the medical sciences 5 35385711
2023 circROCK1 Promotes septic myocardial injury through regulating miR-96-5p/OXSR1 axis. Acta biochimica Polonica 4 37721476
2026 The WNK-OXSR1 osmosensing pathway mediates intestinal regeneration via Hippo-YAP signaling. The EMBO journal 0 41851502

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